This proposed research extends and expands our laboratory's studies on the mechanism of action and design of alkylating antitumor agents. We plan to develop further the trialkylnitrosoureas. These compounds are analogs of BCNU which were designed and synthesized in our laboratory, require metabolic transformation to be active, and show an excellent antitumor effect in animal testing. We propose to investigate the mechanism of activation and to synthesize and test new trialkylnitrosoureas. We also propose to synthesize and test nitrosoureas which have been designed to be metabolically activated by reactions other than dealkylation. The structures of these agents have been based on our knowledge of the structural requirements for nitrosourea activity and on known metabolic pathways. Another group of novel nitrosoureas which we plan to synthesize and test are nitrosoureas bound to carriers, such as acridine, which will bind selectively to DNA.